Protective Effects of Ruitn and / or Hesperidin Against Doxorubicin-Induced Hepatotoxicity

Walaa G. Hozayen^1, , Howida S. Abou Seif² and Susan Amin³

¹Biochemistry Department, Faculty of Science, Beni-Suef University

²Medical Physiology Department, National Research Center, Cairo, Egypt

³University of Connecticut Health Center, Farmington Avenue Farmington, Connecticut, USA

Cite this paper:
Walaa G. Hozayen, Howida S. Abou Seif and Susan Amin. Protective Effects of Ruitn and / or Hesperidin Against Doxorubicin-Induced Hepatotoxicity. International Journal of Clinical Nutrition. 2014; 2(1):11-17. doi: 10.12691/ijcn-2-1-2

Abstract

The present study was conducted to evaluate the protective role of rutin and hesperidin on experimental doxorubicin induced hepatotoxicity. Doxorubicin (DXR) administered rats (25 mg / kg; three times intraperitoneally / week for two weeks) were pretreated with rutin, hesperidin, or their mixture (50 mg / kg body weight) three times per week for three weeks. Results showed that DXR caused a marked rise in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) activities alongside an increase in serum total bilirubin, α-fetoprotein (AFP) and sialic acid levels Concerning oxidative stress and antioxidant defense system, the depleted hepatic glutathione content of DXR-administered rats was increased above normal levels as a result of pretreatment with rutin, hesperidin and both rutin and hesperidin. However, while elevated lipid peroxidation was noticed in DXR treated rats, pretreatment with rutin, hesperidin or both produced a detectable decrease in the lipid peroxidation level. Taken these data together, it can be concluded that natural plant components such as Rutin and Hesperidin could protect the liver against DXR-induced liver toxicity.

Keywords:
rutin hesperidin hepatotoxicity oxidative stress

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References:

[1]	Singal JK and Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 2008; 339; 900-905.
[2]	Cainelli F. and Vallone A. Safety and efficacy of pegylated liposomal doxorubicin in HIV-associated Kaposi’s sarcoma. Biologics 2009; 3; 385-389.
[3]	Ray SD, Balasubramanian G. Raje R, Reid VE, Reddy CS and Bagchi D. Doxorubicin-induced hepatotoxicity may involve apoptotic cell death by modulating expression of Bcl-xL and p 53. Toxicological Scs. 4 2000; 100 (Society of Toxicology meeting abstract # 530).
[4]	Ray SD. Oxidative stress orchestrates both apoptosis & necrosis in vivo: a new perspective from molecular toxicology. In: Galaris, D. (Ed.), Proc. Of Meeting of the Society of Free Radical Research 2003; Medimond Int. Publishers, Italy; pp. 45-53.
[5]	Ray SD and Mehendale H. Apoptosis, In: Wexler, Philip (Ed.), 2nd Edition. Encyclopedia of Toxicology 2000; I. Elsevier Science Publishing, pp. 153-178.
[6]	Kalender Y, Yel M and Kalender S. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats, the effects of vitamin E and catechin. Toxicology 2001; 209; 39-45.
[7]	Zhang FY, Du GJ and Zhang L. Naringenin enhances the anti-tumor effect of Doxorubicin through selectively inhibiting the activity of multidrug resistance associated proteins but not P-glycoprotein. Pharm. Res 2009; 26; 914-925.
[8]	Václavíková R, Kondrová E, and Ehrlichová M. The effect of flavonoid derivatives on Doxorubicin transport and metabolism. Bioorg. Med. Chem 2008; 16; 2034-2042.
[9]	Nabekura T, Yamaki T, Ueno K and Kitagawa S. Inhibition of P-glycoprotein and multidrug resistance protein 1 by dietary phytochemicals. Cancer Chemother. Pharmacol 2008; 62; 867-873.
[10]	Danz ED, Skramsted J, Henry N, Bennett JA and Keller RS. Resveratrol prevents Doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. Free Radic. Biol. Med 2009; 46; 1589-1597.
[11]	Panda S. and Kar A. Periplogenin-3-O-D-glucopyranosyl-(1-N6)-D-glucopyaranosyl-(1–N4)-D-cymaropyranoside, isolated from Aegle marmelos protects Doxorubicin induced cardiovascular problems and hepatotoxicity in rats. Cardiovasc. Ther 2009; 27; 108-116.
[12]	Domitrović R, Jakovac H, Tomac J and Sain I. Liver fibrosis in mice induced by carbon tetrachloride and its reversion by luteolin. Toxicol. Appl. Pharmacol 2009; 241: 311-321.
[13]	Ogawa Y, Kondo T, Sugiyama S, Ogawa K, Satake T and Ozawa T. Role of phospholipase in the genesis of Doxorubicin-induced cardiomyopathy in rats. Cancer Res 1987; 47: 1239-1243.
[14]	Kimura T, Fujita I and Itoh N. Metallothionein act as a cytoprotectant against doxorubicin toxicity. J. Pharmacol. Exp. Ther 2000; 292: 299-302.
[15]	El-Shitany NA, El-Haggar S and El-desoky K. Silymarin prevents Adriamycin induced cardiotoxicity and nephrotoxicity in rats. Food Chem. Toxicol 2008; 46: 2422-2428.
[16]	Quiles J, Huertas J, Battino M, Mataix J and Ramirez-Tortosa M. Antioxidant nutrients and adriamycin toxicity. Toxicology 2002; 180: 79-95.
[17]	Yagmurca M, Erdogan H, Iraz M, Songur A, Ucar M and Fadillioglu E. Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin. Chim. Acta 2004; 348 (1-2): 27-34.
[18]	Luo HN, Jiang NB, King SM. and Chen CY “Inhibition of Cell Growth and VEGF Expression in Ovarian Can Cells by Flavonoids”. Nutrition and Cancer 2008; 60 (6): 800-809.
[19]	Patel N, Joseph C, Corcoran GB and Ray SD. Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p 53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol Appl Pharmacol 2010; 245 (2): 143-52.
[20]	Guardia T, Rotelli AE, Juarez AO and Pelzer LE. “Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat.” I l Farmaco 2001; 56 (9): 683-687.
[21]	Chow JM, Shen SC, Huan SK, Lin HY and Chen YC “Quercetin, but not rutin and quercitrin, prevention of H2O2-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages”, Biochem. Pharmacol 2005; 69 (12): 1839-1851.
[22]	Tsuda H, Uehara N, Iwahori Y, Asamoto M, Iigo M and Nagao M. Chemopreventive effects of beta-carotene, alpha-tocopherol and five naturally occurring antioxidants on initiation of hepatocarcinogenesis by 2-amino-3-methylimidazo [4, 5-f] quinoline in the rat. Japan. J. Cancer Res 1994; 85 (12): 1214-1219.
[23]	Sanchez-Perez L, Kottke T, Diaz RM, Ahmed A, Thompson J, Chong H, Melcher A, Holmen S, Daniels G. and Vile RG. Potent selection of antigen loss variants of B 16 melanoma following inflammatory killing of melanocytes in vivo. Cancer Res 2005; 65 (5): 2009-2017.
[24]	Denda A, Endoh T, Tang Q, Tsujiuchi T, Nakae D and Konishi Y. Prevention by inhibitors of arachidonic acid cascade of liver carcinogenesis, cirrhosis and oxidative DNA damage caused by a choline-deficient, L-amino acid-defined diet in rats. Mutat. Res 1998; 402: 279-288.
[25]	Farombi EO, Shrotriya S, Na HK, Kim SH. and Surh YJ. Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food Chem. Toxicol 2008; 46: 1279-1287.
[26]	Emim JA, Oliveira AB and Lapa AJ. “Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice”. J. Pharm. Pharmacol 1994; 46 (2): 118-22.
[27]	Tanaka T, Kohno H, Tsukio Y, Honjo S, Tanino M, Miyake M. Citrus limonoids obacunone and limonin inhibit azoxymethane-induced colon carcinogenesis in rats. Biofactors 2000; 13: 213-218.
[28]	Canadian Council on Animal Care (CCAC) Guide to the care and use of experimental animals. 1993; Vol. 2. CCAC. Ottawa. Ontario, Canada pp. 1-298.
[29]	Selvakumar E, Prahalathan C, Sudharson.P.T, Viralakshmi. P. Protective effect of lipoic acid on micronuclei induction by cyclophosphamide. Arch. Toxicol 2006; 80 (2): 115-9.
[30]	Fernandes AAH, Novelli ELB, Okoshi K, Okoshi MP, Di Muzio BP, Guimarães JFC, Fernandes A. Influence of rutin treatment on biochemical alterations in experimental diabetes. Biomedicine & Pharmacotherapy 2010; 64 (3): 214-219.
[31]	Yeh MH, Kao ST, Hung CM, Liu CJ, Yeh KLC. Hesperidin inhibited acetaldehyde-induced matrix metalloproteinase-9 gene expression in human hepatocellular carcinoma cells. Toxicology Letters 2009; 184 (3): 204-210.
[32]	Walter M. and Gerad H. Microchem. J 1979; 15; 231.
[33]	Mizejewski GJ. “Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants”. Experimental biology and medicine (Maywood, N.J.) 2001; 226 (5): 377-408.
[34]	Reitman A. and Frankel S. Amer. J. Clin. Path 1957; 28: 56.
[35]	Belfield A, Goldberg D. Colorimetric determination of alkaline phosphatase activity. Enzyme 1971; 12: 561-566.
[36]	Szasz G. Clin. Chem 1969; 22: 124-136.
[37]	Doumas BT. Clin. Chem. Acta. 1971; 31-87.
[38]	Warren L. The thiobarbituric acid assay for sialic acid. J. Biol. Chem 1959; 234: 1971-1976.
[39]	Beutler E, Duron O. and Kelly BM. Improved method for determination of blood glutathione. J. Lab. Clin. Med 1963; 61: 882-888.
[40]	Preuss HG, Jarrel ST, Scheckenbach S. and Anderson RA. Coparative effects of chromium, vanadium and Gymnema sylvestre on sugar induced blood pressure elevations in SHR. J. Coll. Nutr 1998; 17 (2): 116-123.
[41]	Cohen G, Dembiec D. and Marcus J. Measurement of catalase activity in tissues extracts. Anal. Biochem 1970; 34: 30-38.
[42]	Matkovics B, Kotorman M, Sz Varga I, Quy Hai D. and Varga C. Oxidative stress in experimental diabetes induced by streptozotocin. Acta Physiol. Hung 1998; 85 (1): 29-38.
[43]	Mannervik B. and Gutenberg C. Glutathione transferase (Human placenta), Meth. Enzymol 1981; 77: 231-235.
[44]	PC-STAT One-way analysis of variance. Version 1 A (C) copyright. The University of Georgia. Programs coded by Roa, M.; Blane K. and Zonneberg, M. University of Georgia 1985, USA.
[45]	Bose R, Verheij M, Haimovitz-Friedman A, Scotto A, Fuks Z. and Kolesnick RN. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 1995; 82: 405-414.
[46]	Lorenzo E, Ruiz-Ruize C, Quesada A, Hernandez G, Rodriguez A, Lopez-Rivas A. and Redondo J. Doxorubicin induce apoptosis and CD 95 gene expression in human primary endothelial cells through a p 53-depenent mechanism. J. Biol. Chem 2002; 277: 10883-10892.
[47]	Chen H, Yu YY, Zhang M J, Deng XX, Yang WP, Ji J, Peng CH. and Li HW. Protective effect of doxorubicin induced heat shock protein 72 on cold preservation injury of rat livers. World Journal Gastroenterol 2004; 10 (9): 1375-1378.
[48]	Anandakumar PP, Malarkodi SP, Sivaprasad TR. and Saravanan GD. Antioxidant DL-alpha lipoic acid as an attenuator of Adriamycin induced hepatotoxicity in rat model. Indian J Exp Biol 2007; 45 (12): 1045-1049.
[49]	Ajith TA, Aswathy MS and Hema U. The Protective effect of Zingiber officinale roscoe against anticancer drug doxorubicin-induced acute nephrotoxicity. Food and Chemical Toxicology 2008; 46: 3178-3181.
[50]	Wilhelm M, Jaeger DE, Schall-Cablitz H, Hafner D and Idel H. Hepatic clearance and retention of aluminum: studies in the isolated perfused rat liver. Toxicol. Lett 1996; 89 (3): 257-263.
[51]	McNulty TJ and Taylor CW. Extracellular heavy metal ions stimulate Ca2+ mobilization in epatocytes. J. Biochem 1999; 339: 555-561.
[52]	Sies H. Glutathione and its role in cellular functions. Free Radic. Biol. Med 1999; 27: 916-921.
[53]	Tang Q, Denda A, Tsujiuchi T, Tsutsumi M, Amanuma T. and Murata Y. et al. Inhibitary effects of inhibitors of arachidonic acid metabolism on the evolution of rat liver preneoplastic foci into nodules and hepatocellular carcinomas with or without phenobarbital exposure. Jpn. J. Cancer Res 1993; 84: 120-127.
[54]	Hirose M, Takahashi S, Ogawa K, Futakuchi M and Shirai T. Phenolics: blocking agents for heterocyclic amine-induced carcinogenesis. Food Chem. Toxicol 1999 a; 37: 985-992.
[55]	Hirose M, Takahashi S, Ogawa K, Futakuchi M, Shirai T and Shibutani M. et al. Chemoprevention of heterocyclic amine-induced carcinogenesis by phenolic compounds in rats. Cancer Lett 1999 b; 143: 173-178.
[56]	Duthie SJ, Johnson W. and Dobson VL. The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 1997; 390: 141-151.
[57]	Ramos S, Alia M, Bravo L and Goya L. Comparative effects of food-derived polyphenols on the viability and apoptosis of a human hepatoma cell line (Hep G2). J Agric Food Chem 2005; 53: 1271-1280.
[58]	Yuan, ZP, Chen LJ, Fan LY, Tang MH, Yang GL. and Yang HS et al. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin Cancer Res 2006; 12: 3193-3199.
[59]	Van-Rijn J and Van-den-Berg J. Flavonoids as enhancers of x-ray-induced cell damage in hepatoma cells. Clin Cancer Res 1997; 3: 1775-1779.
[60]	Seaton TA, Cooper JM. and Schapira AH. Cyclosporin inhibition of apoptosis induced by mitochondrial complex I toxins. Brain Res 1998; 809: 12-17.
[61]	Esterline RL, Ray SD and Ji S. Reversible and irreversible inhibition of hepatic mitochondrial respiration by acetaminophen and its toxic metabolite, N-acetyl-pbenzoquinoneimine (NAPQI). Biochem. Pharmacol. 1998; 38: 2387-2390.
[62]	Wallace KB. Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc. Toxicol 2007; 7: 101-107.
[63]	Mukhopadhyay P, Rajesh M, Bátkai S, Kashiwaya Y and Haskó G et al. Role of superoxide, nitric oxide, and peroxynitrite in Doxorubicin-induced cell death in vivo and in vitro. Am. J. Physiol. Heart Circ. Physiol. 2009; 296: H 1466-H 1483.
[64]	Bradham CA, Qian T, Streetz K et al. The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol. Cell. Biol 1998; 18: 6353-6364.
[65]	Childs AC, Phaneuf SL, Dirks AJ Phillips T and Leeuwenburgh C. Doxorubicin treatment in vivo causes cytochrome c release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2: Bax ratio. Cancer Res 2002; 62: 4592-4598.
[66]	Xu Z, Lin S. and Wu W, et al. Ghrelin prevents Doxorubicin-induced cardiotoxicity through TNF-alpha / NF-kappaB pathways and mitochondrial protective mechanisms. Toxicology 2008: 247: 133-138.
[67]	Parra V, Eisner V, Chiong M and Criollo A, et al. Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc. Res 2008; 77: 387-397.
[68]	Sung B, Kunnumakkara AB. and Sethi G, et al. Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model. Mol. Cancer Ther 2009; 8: 959-970.
[69]	Tasduq SA, Peerzada K and Koul S et al. Biochemical manifestations of antituberculosis drugs induced hepatotoxicity and the effect of silymarin. Hepatol. Res 2005; 31: 132-135.